title: Selective cyclooxygenase-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation.
abstract: OBJECTIVE
  The use of cyclooxygenase-2 (COX-2) inhibitors has been reported to be associated with detrimental vascular events. The aim of our study was to evaluate the role of COX-2 activity in the control of human vascular tone under inflammatory conditions.
  
  
  RESULTS
  Using organ bath experiments, the contraction induced by norepinephrine (NE), U46619, acetylcholine, and KCl was performed on isolated human internal mammary arteries (IMA) cultured in the presence or absence of both interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS) with or without endothelium. Under these conditions the COX (cyclooxygenase) isoforms were detected by immunohistochemistry and western blot, and the prostaglandins (PG) and thromboxane (Tx) released were measured using an enzyme immunoassay kit. A significant decrease in the maximal effect induced by NE but not by other stimuli was observed in the IL-1beta- and LPS-treated preparations after 6 and 24 h of culture (-19 +/- 6 and -25 +/- 4%, respectively), an effect that was endothelium independent. Under this inflammatory condition, the COX-2 inhibitors DFU (1 micromol/L), DuP-697 (0.5 micromol/L), and Etoricoxib (1 micromol/L) markedly restored and increased the vascular reactivity to NE. These alterations were not observed with SC-560 (1 micromol/L), a selective COX-1 inhibitor. In addition, the COX-1 isoform was always detected and the COX-2 isoform was only found in human IMA exposed for 6 or 24 h under inflammatory conditions. The COX-2 induction was accompanied by an increase in PGE(2) (prostaglandin E(2)) and PGI(2) (prostaglandin I(2)) release in the culture medium (approximately 2.5-fold) but not with an increase in TxA(2) (thromboxane A(2)) release.
  
  
  CONCLUSIONS
  These observations suggest that the inhibition of COX-2 directly potentiates the human vascular tone induced by NE under inflammatory conditions.
authors.affiliation: INSERM U698: Haemostasis, Bio-engineering and Cardiovascular Remodeling, CHU X. Bichat, 46, rue Henri Huchard, Paris 75018, France.
authors.forename: Nabil
authors.initials: N
authors.lastname: Foudi
authors.forename: Liliane
authors.initials: L
authors.lastname: Louedec
authors.forename: Thierry
authors.initials: T
authors.lastname: Cachina
authors.forename: Charles
authors.initials: C
authors.lastname: Brink
authors.forename: Xavier
authors.initials: X
authors.lastname: Norel
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000378:metabolism; D000208:Acute Disease; D000368:Aged; D051545:Cyclooxygenase 1 / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000032:analysis; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology*; D009924:Organ Culture Techniques; D013929:Thromboxane B2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D015232:Dinoprostone; D009638:Norepinephrine